Targeted delivery of tumor necrosis factor in combination with lomustine induces a T-cell dependent regression of glioblastoma

Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here we report that the combination of L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes on the tumor neo-vasculature, with the alkylating agent lomustine, can induce tumor regression in orthotopic glioma-bearing mice and patients with recurrent glioblastoma. Mechanistically, this striking synergy crucially depended on T cells and involved activation of the tumor endothelium, tumor DNA damage, treatment-associated tumor necrosis, increased antigen presentation on MHC class I and tumor immune cell infiltration, as well as decreased tumor-associated immunosuppression. The clinical translation of this approach is ongoing, but already shows durable responses in the first recurrent glioblastoma patient cohort treated with L19TNF in combination with lomustine (NCT04573192).